Simple One-pot Conversion of Aldehydes and Ketones to Enals

Abstract

A simple and efficient method to convert aldehydes into α,β-unsaturated aldehydes with a two-carbon homologation is presented. Hydroboration of ethoxy acetylene with BH 3 •SMe 2 generates tris (ethoxyvinyl) borane. Transmetallation with diethylzinc, addition to aldehydes or ketones, and acidic workup affords enals. When the addition is quenched with anilinium hydrochloride, 1,2-dithioglycol, or acetic anhydride the unsaturated imine, dithiolane, or 1,1-diacetate is isolated in high yield. These transformations can be performed in a one-pot procedure.The field of organocatalysis has witnessed explosive growth in the last decade and will continue to be a dynamic area of chemical research. 1 A wide variety of organocatalysts and reaction classes have been recently advanced, and many of these are based on α,β-unsaturated aldehydes as substrates. As a result, enals have arguably become the single most important class of substrates for development and applications of organocatalytic transformations 2 while remaining a mainstay of metal-based catalytic asymmetric processes. 1a,3 To keep pace with the ever-increasing demand for enals, current synthetic methods must be reevaluated and optimized or supplanted with new, direct and more efficient approaches. Herein we disclose a simple and practical yet broadly applicable one-pot method for the conversion of aldehydes and ketones into α,β-unsaturated aldehydes.A practical synthesis of enals would meet the following criteria: it must be general, employ commercially available and inexpensive reagents, use common laboratory techniques, be functional group compatible, and be tolerant of α-stereogenic centers in enantioenriched aldehydes and ketones. Furthermore, the transformation should be amenable to a one-pot procedure to enable rapid generation of an array of enals.Existing methods for conversion of aldehydes and ketones to enals do not satisfy these criteria (Scheme 1). For example, cross aldol reactions with acetaldehyde enolates are not general, yielding self-condensation products with aliphatic aldehyde partners (Scheme 1, A). 4 This difficulty can be circumvented with C-silated imines (B and C), 5 but these imines must be prepared, silylated, and distilled, adding additional steps. Methods employing commercially available ethoxy acetylene are most attractive (Scheme 1, E and F). Hydrostannylation of ethoxy acetylene provides a vinylstannane. Transmetallation with n-BuLi leads to a highly reactive vinyllithium that readily adds to aldehydes and ketones to afford enals on acidic workup. 9 The drawback of such methods is the incompatibility of the vinyllithium with most functional groups. Suzuki introduced a method that combines the twosteps above into one and circumvents the highly reactive vinyllithium intermediate in E. 10 Thus, hydrozirconation of ethoxy acetylene, in situ transmetallation of the vinylzirconocene intermediate with catalytic AgClO 4 , addition to aldehydes and elimination provides enals (F). Although this method has advantages over those outl...

Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

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Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV

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Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from α,β-unsaturated aldehydes for enantioselective Diels–Alder reactions

“…The use of isolated ketenes and α-aryloxy aldehydes adds several steps to the preparation of the starting materials. We therefore sought to use α,β-unsaturated aldehydes as substrates, as these compounds are widely employed in a variety of enantioselective organocatalytic reactions and they are increasingly commercially available or readily prepared by improved methods (30). Although this has proven possible in carefully designed intramolecular systems, such as those reported by Scheidt and co-workers (31), the use of simple α,β-unsaturated aldehydes as ester enolate precursors has not been achieved.…”